Tumor–immune metabolic tug-of-war: from immune escape to targeting metabolic rewiring in cancer therapy

Cancer remains one of the leading causes of death worldwide, with nearly 20 million new cases and 9.7 million deaths reported in 2022. Projections estimate that annual incidence may increase to 35 million by 2050, underscoring cancer as both a biomedical challenge and a global socioeconomic burden. A key hallmark of malignancy that sustains this progression is metabolic reprogramming. Within the nutrient- and oxygen-deprived tumor microenvironment, cancer cells rewire their metabolism to generate the energy and biosynthetic intermediates necessary for unchecked proliferation, invasion, and metastasis. This metabolic adaptation, however, extends beyond tumor growth. By competing for critical nutrients such as glucose and glutamine, cancer cells establish a metabolic tug-of-war with immune cells, impairing their activation and antitumor functions. In addition, cancer cells produce oncometabolites that act as signaling molecules, fostering immune suppression. Together, nutrient competition and oncometabolite signaling contribute to immune evasion and therapeutic resistance. In this review, we examine the dynamic metabolic dialogue between tumors and the immune system, focusing on how cancer cells induce immune metabolic rewiring, how immune cells respond or succumb to these changes, and the therapeutic opportunities emerging from targeting metabolic vulnerabilities on both sides of the tug-of-war.